Method for preparing 2-amino-5-chloro-n,3-dimethylbenzamide

Abstract

A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, including: subjecting o-toluidine to acylation reaction with an acylation agent to obtain o-methylacetanilide; subjecting the o-methylacetanilide to chlorination reaction with a chlorination agent to obtain 4-chloro-2-methylacetanilide; subjecting the 4-chloro-2-methylacetanilide to oximation reaction with an oximation agent to obtain 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide; subjecting the 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide to cyclization reaction with sulfuric acid to obtain 5-chloro-7-methylisatin; subjecting the 5-chloro-7-methylisatin to oxidation reaction with an oxidation agent to obtain 5-chloro-7-methylisatoic anhydride; and subjecting the 5-chloro-7-methylisatoic anhydride to ammonolysis reaction with monomethylamine to obtain the 2-amino-5-chloro-N,3-dimethylbenzamide

What is claimed is: 
     
         1 . A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, comprising the following steps:
 subjecting o-toluidine to acylation reaction with an acylation agent to obtain o-methylacetanilide, as shown in the following equation:   
       
         
           
           
               
               
           
         
         subjecting the o-methylacetanilide to chlorination reaction with a chlorination agent to obtain 4-chloro-2-methylacetanilide, as shown in the following equation: 
       
       
         
           
           
               
               
           
         
         subjecting the 4-chloro-2-methylacetanilide to oximation reaction with an oximation agent to obtain 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide, as shown in the following equation: 
       
       
         
           
           
               
               
           
         
         subjecting the 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide to cyclization reaction with sulfuric acid to obtain 5-chloro-7-methylisatin, as shown in the following equation: 
       
       
         
           
           
               
               
           
         
         subjecting the 5-chloro-7-methylisatin to oxidation reaction with an oxidation agent to obtain 5-chloro-7-methylisatoic anhydride, as shown in the following equation: 
       
       
         
           
           
               
               
           
         
       
       and
 subjecting the 5-chloro-7-methylisatoic anhydride to ammonolysis reaction with monomethylamine to obtain the 2-amino-5-chloro-N,3-dimethylbenzamide, as shown in the following equation: 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein the subjecting o-toluidine to acylation reaction with an acylation agent to obtain o-methylacetanilide comprises:
 adding the acylation agent to a solution of the o-toluidine under stirring, and performing the acylation reaction at a first preset reaction temperature until the acylation reaction is completed, to obtain a first reaction system; and subjecting the first reaction system to cooling, suction filtration, water-washing, and oven-drying to obtain the o-methylacetanilide,   wherein the solution of the o-toluidine comprises at least one solvent selected from the group consisting of dichloromethane, dichloroethane, acetic acid, acetic anhydride, chlorobenzene, and xylene; the acylation agent is acetic acid or acetic anhydride; a molar ratio of the o-toluidine to the acylation agent is in a range of 1:0.9 to 1:1.5; a molar ratio of the o-toluidine to the solvent in the solution of the o-toluidine is in a range of 1:3 to 1:7; and the first preset reaction temperature is in a range of −10° C. to 135° C.   
     
     
         3 . The method of  claim 1 , wherein the subjecting the o-methylacetanilide to chlorination reaction with a chlorination agent to obtain 4-chloro-2-methylacetanilide comprises:
 adding the chlorination agent to a solution of the o-methylacetanilide under stirring, and performing the chlorination reaction at a second preset reaction temperature until the chlorination reaction is completed, to obtain a second reaction system; and subjecting the second reaction system to cooling, suction filtration, and oven-drying to obtain the 4-chloro-2-methylacetanilide,   wherein a solvent in the solution of the o-methylacetanilide is at least one selected from the group consisting of methanol, ethanol, dichloromethane, dichloroethane, acetic acid, chlorobenzene, and water; the chlorination agent is at least one selected from the group consisting of chlorine gas, N-chlorosuccinimide (NCS), hydrogen peroxide/hydrochloric acid, oxygen gas/hydrochloric acid, sulfuryl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and sodium hypochlorite; a molar ratio of the o-methylacetanilide to the chlorination agent is in a range of 1:1.1 to 1:1.5; a molar ratio of the o-methylacetanilide to the solvent in the solution of the o-methylacetanilide is in a range of 1:3 to 1:8; and the second preset reaction temperature is in a range of −10° C. to 105° C.   
     
     
         4 . The method of  claim 1 , wherein the subjecting the 4-chloro-2-methylacetanilide to oximation reaction with an oximation agent to obtain 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide comprises:
 adding the oximation agent to a solution of the 4-chloro-2-methylacetanilide under stirring, and performing the oximation reaction at a third preset reaction temperature until the oximation reaction is completed, to obtain a third reaction system; and subjecting the third reaction system to suction filtration, water-washing, and oven-drying to obtain the 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide,   wherein a solvent in the solution of the 4-chloro-2-methylacetanilide is selected from the group consisting of methanol, ethanol, dichloromethane, dichloroethane, acetic acid, chlorobenzene, and water; the oximation agent is selected from the group consisting of methyl nitrite, ethyl nitrite, n-butyl nitrite, isopropyl nitrite, isoamyl nitrite, and n-amyl nitrite; a molar ratio of the 4-chloro-2-methylacetanilide to the oximation agent is in a range of 1:1.1 to 1:2.0; a molar ratio of the 4-chloro-2-methylacetanilide to the solvent in the solution of the 4-chloro-2-methylacetanilide is in a range of 1:3 to 1:20; and the third preset reaction temperature is in a range of −10° C. to 115° C.   
     
     
         5 . The method of  claim 1 , wherein the subjecting the 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide to cyclization reaction with sulfuric acid to obtain 5-chloro-7-methylisatin comprises:
 adding the 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide to an aqueous solution of the sulfuric acid under stirring, and performing the cyclization reaction at a fourth preset reaction temperature until the cyclization reaction is completed, to obtain a fourth reaction system; and subjecting the fourth reaction system to cooling, suction filtration, and oven-drying to obtain the 5-chloro-7-methylisatin,   wherein a concentration of the aqueous solution of the sulfuric acid is 75 wt % to 98 wt %; a molar ratio of the 4-chloro-2-(hydroxyimino)-N-(2-methylphenyl) acetamide to the sulfuric acid is in a range of 1:3 to 1:30; and the fourth preset reaction temperature is in a range of 20° C. to 115° C.   
     
     
         6 . The method of  claim 1 , wherein the subjecting the 5-chloro-7-methylisatin to oxidation reaction with an oxidation agent to obtain 5-chloro-7-methylisatoic anhydride comprises:
 adding the oxidation agent dropwise to a solution of the 5-chloro-7-methylisatin under stirring, and performing the oxidation reaction at a fifth preset reaction temperature until the oxidation reaction is completed, to obtain the fifth reaction system; and subjecting the fifth reaction system to cooling, suction filtration, water-washing, and oven-drying to obtain the 5-chloro-7-methylisatoic anhydride,   wherein the oxidation agent is at least one selected from the group consisting of hydrogen peroxide, peroxyacetic acid, n-butanol peroxide, chromium trioxide, potassium permanganate, sodium hypochlorite, potassium chlorate, potassium peroxymonosulfate, and sodium persulfate; a molar ratio of the 5-chloro-7-methylisatin to the oxidation agent is in a range of 1:1.1 to 1:2.1; and the fifth preset reaction temperature is in a range of −10° C. to 110° C.   
     
     
         7 . The method of  claim 1 , wherein the subjecting the 5-chloro-7-methylisatoic anhydride to ammonolysis reaction with monomethylamine to obtain the 2-amino-5-chloro-N,3-dimethylbenzamide comprises:
 adding an aqueous solution of the monomethylamine dropwise to a solution of the 5-chloro-7-methylisatoic anhydride under stirring, and performing the ammonolysis reaction at a sixth preset reaction temperature until the ammonolysis reaction is completed, to obtain the sixth reaction system; and subjecting the sixth reaction system to suction filtration, water-washing, and oven-drying to obtain the 2-amino-5-chloro-N,3-dimethylbenzamide,   wherein a concentration of the aqueous solution of the monomethylamine is in a range of 10 wt % to 40 wt %; a solvent in the solution of the 5-chloro-7-methylisatoic anhydride is at least one selected from the group consisting of methanol, ethanol, dichloromethane, dichloroethane, acetonitrile, ethyl acetate, and water; a molar ratio of the 5-chloro-7-methylisatoic anhydride to the monomethylamine is in a range of 1:1.1 to 1:3.1; and the sixth preset reaction temperature is in a range of −10° C. to 110° C.